Infection of a naive (non-immune) host with a virus elicits an immediate cellular response termed the innate immune response of the interferon response. Many viruses have evolved to counteract this host defense mechanism. The focus of this grant is to gain a general understanding of how influenza A and B viruses modulate the innate defenses of the host. Virus infection activates cellular functions (presumably through dsRNA) that promote the de novo transcription of antiviral genes, including type I interferon. Interferon is released from the cell and through signal transduction induces the transcription of interferon responsive genes (ISGs) in an autocrine and paracrine manner. Newly synthesized proteins set up an antiviral state in uninfected adjacent cells to limit virus replication in subsequent rounds of infection. In addition, interferon synthesized by professional antigen presenting cells may determine the type of adaptive immunity (TH1/TH2) developed by the host. We recently discovered that the influenza A virus NS1 protein functions to limit the antiviral effects of interferon. A virus which lacks NS1 (de1NS1) replicates poorly in interferon-competent hosts but replicates well (and is pathogenic) in transgenic mouse lines which are defective in interferon signaling of transcription. The interaction between the host and influenza A and B viruses during an interferon response to the virus will be examined. Important questions addressed by the five laboratories participating in this program project grant include: (1) What are the structural requirements in the NS1 protein which enable influenza A and influenza B viruses to counteract the innate immune response of the host? (2) What is the precise molecular mechanism for suppression of the interferon response by influenza virus NS1 proteins? (3) Does deletion or modification of the NS1 gene result in better activation of dendritic cells and consequent stimulation of a TH1 type immune response? (4) Does interferon play a role in the tissue tropism of influenza viruses? (5) Does deletion of the NS1 gene attenuate influenza virus virulence in humans? The goal of this program project grant is to gain new insights into virus modulation of the host interferon response. It is hoped that these efforts may lead to a novel influenza virus vaccine approach based on modifications of the interferon antagonist NS1 protein.